CHICAGO – About half of men with castration-resistant prostate cancer demonstrated considerable declines in prostate-specific antigen levels when treated with the investigational agent galeterone in a phase I dose-escalation trial, investigators reported.
Galeterone (TOK-001), an orally available, semisynthetic steroid analogue, mounts a three-pronged attack on prostate cancer, according to Dr. R. Bruce Montgomery of the University of Washington in Seattle. It inhibits CYP17 lyase (a key enzyme in the androgen production pathway in the disease), inhibits androgen-receptor binding, and disrupts internal androgen-receptor production in prostate cancer cells.
Dr. R. Bruce Montgomery
This novel triple-target mechanism, which was identified in preclinical studies, "could help prevent drug resistance," Dr. Montgomery said during a press briefing at the annual meeting of the American Association for Cancer Research, where the data were presented.
To evaluate the safety and efficacy of the drug, Dr. Montgomery and his colleagues enrolled 49 men with metastatic and nonmetastatic, chemotherapy-naive, castration-resistant prostate cancer (CRPC) in the ARMOR1 trial sponsored by Tokai Pharmaceuticals.
All of the men, who ranged in age from 48-93 years, had an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1, as well as disease progression during androgen ablation therapy. Exclusion criteria included prior treatment with ketoconazole, MDV3100, abiraterone (Zytiga), sipuleucel-T (Provenge), TAK-700, mitoxantrone (Novantrone), or chemotherapy based on either docetaxel (Taxotere) or cabazitaxel (Jevtana).
The study participants were randomized to eight dose-escalation cohorts that received single or split daily doses of galeterone ranging from 650 mg to 2,600 mg per day for 12 weeks, followed by optional continuation in an extension phase, Dr. Montgomery explained.
Efficacy was a secondary outcome measure, which was assessed based on change in PSA level, changes from baseline in CT/MRI and bone scans, RECIST (Response Evaluation Criteria in Solid Tumors) data, and laboratory measures.
A majority of patients had PSA reductions; among them, 11 patients had PSA reductions of at least 50% and an additional 13 patients had PSA reductions of 30%-49%, reported Dr. Montgomery, noting that the magnitude of the reductions were dose related. In addition, some patients had evidence of a reduction in tumor size on CT scans.
"The improved PSA response indicates that the drug is getting to the target, because PSA expression is controlled by the androgen receptor," he said in an interview. "The fact that so many patients had a PSA reduction of 30% or more is exceptional in a phase I dose-finding trial."
The primary outcome measures were tolerability and safety, as measured by the incidence of adverse events and the change from baseline in clinical laboratory assessments, physical examination, vital signs, and electrocardiograms, he said.
Grade 1 and 2 adverse events were reported in 58% and 30% of the patients, respectively. These included fatigue (36.7%), abnormal AST tests (32.7%), abnormal ALT tests (30.6%), nausea (28.6%), diarrhea (26.5%), and pruritis (24.5%), Dr. Montgomery reported.
In all, "15 patients had transient grade 2/3 liver-enzyme elevations, including 11 who required dose interruptions," he said.
Of the 11 patients with dose interruptions, 7 resumed galeterone treatment, and 6 completed the treatment without recurrent grade 3 elevations in liver enzymes, he added, noting that "the transaminitis was not dose-related and was very transient."
The finding does suggest, however, that regular monitoring of liver function enzymes may be warranted in men taking the drug, he said.
Of nine serious adverse events reported in the study, only one was linked to galeterone. "The single, related grade 4 adverse event was rhabdomyolysis in a patient with renal insufficiency who was on simvastatin therapy," Dr. Montgomery said. "No cases of adrenal mineralocorticoid excess were observed."
The study did not reveal dose proportionality, but "the maximum tolerated dose was identified at the doses evaluated in the trial," Dr. Montgomery said. Therefore, Tokai Pharmaceuticals is currently reformulating the drug "to optimize pharmacokinetics and pharmacodynamics."
The new formulation will be evaluated later this year in a phase II clinical trial, he said.
Tokai Pharmaceuticals sponsored the trial. Dr. Montgomery disclosed no relevant financial conflicts of interest.